Neural vascular insufficiency plays an important role in diabetic peripheral neuropathy (DPN). Peroxisome proliferative-activated receptor (PPAR)α has an endothelial protective effect related to activation of PPARγ coactivator (PGC)-1α and vascular endothelial growth factor (VEGF), but its role in DPN is unknown. We investigated whether fenofibrate would improve DPN associated with endothelial survival through AMPK-PGC-1α-eNOS pathway. Fenofibrate was given to db/db mice in combination with anti-flt-1 hexamer and anti-flk-1 heptamer (VEGFR inhibition) for 12 weeks. The db/db mice displayed sensory-motor impairment, nerve fibrosis and inflammation, increased apoptotic cells, disorganized myelin with axonal shrinkage and degeneration, fewer unmyelinated fibers, and endoneural vascular rarefaction in the sciatic nerve compared to db/m mice. These findings were exacerbated with VEGFR inhibition in db/db mice. Increased apoptotic cell death and endothelial dysfunction via inactivation of the PPARα-AMPK-PGC-1α pathway and their downstream PI3K-Akt-eNOS-NO pathway were noted in db/db mice, human umbilical vein endothelial cells (HUVECs) and human Schwann cells (HSCs) in high-glucose media. The effects were more prominent in response to VEGFR inhibition. In contrast, fenofibrate treatment ameliorated neural and endothelial damage by activating the PPARα-AMPK-PGC-1α-eNOS pathway in db/db mice, HUVECs and HSCs. Fenofibrate could be a promising therapy to prevent DPN by protecting endothelial cells through VEGF-independent activation of the PPARα-AMPK-PGC-1α-eNOS-NO pathway.

An acute spontaneous spinal epidural hematoma (SSEH) is a rare spinal pathology. A 57-year-old man who had hypertension and had been on dual antiplatelet therapy with aspirin and clopidogrel for primary prevention presented with the sudden onset of mid back pain and monoplegia of the left lower extremity. Magnetic resonance imaging revealed an epidural hematoma, and the patient underwent emergency hemilaminectomy for evacuation. However, the symptoms worsened, and complete paraplegia developed. A second procedure to remove the recurrent hematoma was performed. No vascular malformation or other possible cause for SSEH was found other than the aspirin and clopidogrel medication. This case report describes relapsed SSEH caused by the combination of aspirin and clopidogrel medication and urges caution in prescribing dual antiplatelet agents.

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